This invention relates to the local, differential delivery of nitric oxide within the body.
At present, numerous therapeutic techniques are based on systemic delivery of therapeutic agents. Systemic delivery, however, is not well suited to the treatment of disease entities with a single site of interest. For example, systemic delivery necessitates exposing sites other than the site of interest to medication where the medication may have an adverse reaction. As a result, the agent concentration at the site of interest is often limited by the detrimental effects of the agent at distant sites. Moreover, sufficiently large quantities of agent within the entire volume of the body are required to obtain the desired effect at the desired site. Finally, the agent is exposed to degradation and elimination by an organ system(s) remote from the site of interest. In response to this recognition, numerous techniques and medical articles for the localized delivery of therapeutic agents to the body have been proposed.
Nitric oxide is a gaseous molecule produced constitutively in the body through the enzymatic degradation of L-arginine. Under conditions of oxidative stress, an induced nitric oxide is also produced. Nitric Oxide is a highly reactive free radical, properly represented by NO⋄, however, for purposes of this patent application it will also be represented by xe2x80x9cnitric oxidexe2x80x9d and xe2x80x9cNOxe2x80x9d. Nitric oxide has been shown at lower doses to relax smooth muscle cells (including vascular smooth muscle cells), inhibit vascular smooth muscle cell proliferation, protect endothelial cells from apoptosis, provide anti-thrombogenic and antioxidant effects, and promote wound healing. At higher dosages, it ultimately becomes cytotoxic.
Local delivery of compounds that release or produce nitric oxide has been proposed. However, it is not presently known to locally and differentially deliver nitric oxide to the body. As will become clear below, local differential delivery of nitric oxide to the body is useful in connection with a number of therapeutic strategies.
According to a first aspect of the invention, a medical article is provided, which comprises: (a) a first element comprising a first nitric oxide donor compound, in which the first nitric oxide donor compound is adsorbed to, attached to or disposed within a first composition and (b) a second element comprising a second nitric oxide donor compound, in which the second nitric oxide donor compound is adsorbed to, attached to or disposed within a second composition which is chemically distinct from first composition. The medical article is adapted, after placement at a delivery position on or within the body of a patient, for local delivery of (i) one or more of the first nitric oxide donor compound and a nitric oxide product of the first nitric oxide donor compound and (ii) one or more of the second nitric oxide donor compound and a nitric oxide product of the second nitric oxide donor compound. The first and second nitric oxide donor compounds can be the same or different.
The medical article is preferably used to increase local nitric oxide concentration in the body upon placement of the medical article at the delivery position.
In some embodiments, the medical article is adapted to deliver the first nitric oxide donor compound or a nitric oxide product of the first nitric oxide donor compound to a first tissue and the second element is adapted to deliver the second nitric oxide donor compound or a nitric oxide product of the second nitric oxide donor compound to a second tissue that differs from the first tissue.
Preferably, the first composition is selected from (ia) a first surface to which the first nitric oxide donor compound is adsorbed or attached, (ib) a first polymer matrix within which the first nitric oxide donor compound is disposed, and (ic) a first solution or first fluid dispersion within which the first nitric oxide donor compound is disposed, while the second composition is selected from (iia) a second surface of the medical article to which the second nitric oxide donor compound is adsorbed or attached, (iib) a second polymer matrix within which the second nitric oxide donor compound is disposed, and (iic) a second solution or a second fluid dispersion within which the second nitric oxide donor compound is disposed.
For example, (a) the first composition can be a first polymer matrix and the second composition can be a second, chemically distinct, polymer matrix, (b) the first composition can be a surface and the second composition can be a matrix, (c) the first composition can be a solution or fluid dispersion and the second composition can be a matrix, or (d) the first composition can be a solution or fluid dispersion and the second composition can be a surface.
Where one or more matrices are used, preferred matrix materials include polymers, copolymers and polymer blends comprising polylactic acid, polyurethane and polyalkene components. Moreover, a barrier layer can be disposed over the matrices, where desired. The matrices can be in the form of layers that coat at least a portion of the medical article.
Where two matrices are used, one polymer matrix can be disposed over the other. Moreover, one polymer matrix can be an immediate release polymer matrix and the other matrix can be a sustained release polymer matrix.
In some preferred embodiments, a first period of time (i.e., the time that it takes to release 50 mol % of the first nitric oxide donor compound or a nitric oxide product of the first nitric oxide donor compound from the first element upon placement at the delivery position) ranges from 24 to 48 hours, and a second period of time (i.e., the time that it takes to release 50 mol % of either the second nitric oxide donor compound or a nitric oxide product of the second nitric oxide donor compound from the second element upon placement at the delivery position) ranges from 4 to 6 weeks. In other preferred embodiments, the second period of time is at least 10 times as great as the first period of time.
Numerous medical articles are appropriate for use in connection with the present invention, including vascular medical devices, urological medical devices, biliary medical devices, gastrointestinal medical devices, medical devices adapted for placement at surgical sites, and medical devices adapted for placement on skin wounds or openings.
Numerous nitric oxide donor compounds are appropriate for use in connection with the present invention, including organic nitrates, O-nitrosylated compounds, S-nitrosylated compounds, nonoate compounds, inorganic nitroso compounds, sydnonimines and L-arginine.
According to a second aspect of the invention, a medical article is provided which comprises: (a) a first nitric oxide donor compound; and (b) a second nitric oxide donor compound that differs from the first nitric oxide donor compound. The medical article is adapted, after placement at a delivery position on or within the body of a patient, for local delivery of (i) one or more of the first nitric oxide donor compound and a nitric oxide product of the first nitric oxide donor compound and (ii) one or more of the second nitric oxide donor compound and a nitric oxide product of the second nitric oxide donor compound.
The medical article is typically used to increase local nitric oxide concentration in the body by placing the medical article at the delivery position.
In some preferred embodiments, the first nitric oxide donor compound has a short half-life and the second nitric oxide donor compound has a long half-life. Preferred short half-life compounds are diethylamine nonoate, (E)-2-[(E)-hydroxyimino]-6methoxy-4-methyl-5-nitro-3-hexenamide, 3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo-1-triazene, 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene and nitroso-N-acetylpenicillamine. Preferred long half-life compound are polyethylene glycol-NO-nucleophile hydrogels and polyurethane and poly(vinyl chloride) containing nitric oxide-releasing diazeniumdiolate moieties. Preferably upon placement of the medical article at the delivery position, for example, within the vasculature, the first nitric oxide donor compound has a half-life that is at least 10 times as great as a half-life of the second nitric oxide donor compound.
In some preferred embodiments, the first nitric oxide donor compound has a first mechanism for nitric oxide release, and the second nitric oxide donor compound has a second mechanism for nitric oxide release differing from the second mechanism. Such a medical article can further include a component selected from an amino acid, a metal ion and an enzyme.
As a first example, the first nitric oxide donor compound can be selected to have greater activity than the second nitric oxide donor compound with respect to an action selected from vasodilation, platelet aggregation inhibition, vascular inflammation reduction, smooth muscle proliferation reduction, and endothelial cell protection, while the second nitric oxide donor compound can be selected to have greater activity than the first nitric oxide donor compound with respect to another of these actions. As a more specific example, the first nitric oxide donor compound can be selected to have greater vasodilation activity than the second nitric oxide donor compound, while the second nitric oxide donor compound can be selected to have greater platelet aggregation inhibition activity than the first nitric oxide donor compound.
As a second example, the first and second nitric oxide donor compounds can be selected such that the first nitric oxide donor compound releases nitric oxide at a higher rate than the second nitric oxide donor compound when contacted with a first tissue, and the second nitric oxide donor compound releases nitric oxide at a higher rate than the first nitric oxide donor compound when contacted with a second tissue. More specifically, the compounds can be selected such that the first nitric oxide donor compound releases nitric oxide at a higher rate when contacted with blood, while the second nitric oxide donor compound releases nitric oxide at a higher rate when contacted with vascular tissue.
Preferred first nitric oxide donor compounds are S-nitrosothiol compounds that are directly susceptible to metal ion catalyzed release (for instance, S-nitroso-DL-penicillamine), while preferred second nitric oxide donor compounds are S-nitrosothiol compounds that are substantially susceptible to metal ion catalyzed release only after having been converted to another S-nitrosothiol compound (for instance, S-nitrosoglutathione).
According to another aspect of the present invention a method of treating an atherosclerotic lesion is provided. The method comprises: (a) exposing the lesion to a first concentration of nitric oxide effective to reduce the number of cells within the lesion; and (b) subsequently exposing the lesion to a second concentration of nitric oxide effective to inhibit restenosis, where the second concentration is lower than the first concentration.
Preferably, the lesion is exposed to the first concentration of nitric oxide for a first period ranging from 12 hours to 84 hours, more preferably 24 to 48 hours, while it is exposed to the second concentration of nitric oxide for a second period ranging from 3 to 12 weeks, more preferably 4 to 6 weeks.
The first and second concentrations are preferably provided by a medical device placed at the lesion, such as a stent, infusion catheter, or intraluminal paving device.
In some embodiments, the first and second concentrations are provided by a medical device that comprises: (a) a first nitric oxide donor compound; and (b) a second nitric oxide donor compound, wherein the second nitric oxide donor compound differs from the first nitric oxide donor compound. Upon placement at the lesion, the first nitric oxide donor compound preferably has a half-life that is at least 10 times as great as a half-life of the second nitric oxide donor compound.
In other embodiments, the first and second concentrations are provided by a medical device that comprises: (a) a first element comprising a first nitric oxide donor compound, the first nitric oxide donor compound being adsorbed to, attached to or disposed within a first composition and (b) a second element differing from the first element and comprising a second nitric oxide donor compound, the second nitric oxide donor compound being adsorbed to, attached to or disposed within a second composition which is chemically distinct from the first composition. For instance, the first element can be a first polymer matrix within which the first nitric oxide donor compound is disposed, and the second element can be a second polymer matrix differing from the first polymer matrix within which the second nitric oxide donor compound is disposed. The first and second nitric oxide donor compounds can be the same or different in these embodiments.
According to another aspect of the invention, a method of increasing local nitric oxide concentrations within two or more bodily tissues is provided. The method comprises: (a) providing a medical article comprising a first nitric oxide donor compound and a second nitric oxide donor compound, wherein the first nitric oxide donor compound has a first mechanism for nitric oxide release, and wherein the second nitric oxide donor compound has a second mechanism for nitric oxide release differing from the first mechanism; and (b) placing the medical article at a delivery position on or within the body of a patient.
In some preferred embodiments, the first nitric oxide donor compound releases nitric oxide at a higher rate than the second nitric oxide donor compound when contacted with a first tissue, and the second nitric oxide donor compound releases nitric oxide at a higher rate than the first nitric oxide donor compound when contacted with a second tissue. In others, the first nitric oxide donor compound is an S-nitrosothiol compound (e.g. S-nitroso-DL-penicillamine) that is directly susceptible to metal ion catalyzed release and the second nitric oxide donor compound (e.g., S-nitrosoglutathione) is an S-nitrosothiol compound that is susceptible to substantial metal ion catalyzed release only after being converted to a third S-nitrosothiol compound.
One advantage associated with the present invention is that great flexibility is provided in tailoring the release profile associated with nitric oxide donor compounds and/or nitric oxide itself.
Another advantage is that differing concentrations of nitric oxide donor compounds and/or nitric oxide can be provided at different times from a single medical article.
Another advantage is that differing therapeutic effects can be provided by a single medical article at different times.
Yet another advantage of the present invention is that different therapeutic effects within different tissues can be targeted using a single medical article.
These and other embodiments and advantages of the present invention will become readily apparent to those of ordinary skill in the art upon review of the detailed description and claims to follow.